The type of immune response generated by infection or other antigenic challenge can generally be distinguished by the subset of T helper (Th) cells involved in the response. The Th1 subset is responsible for classical cell-mediated functions such as delayed-type hypersensitivity and activation of cytotoxic T lymphocytes (CTLs), whereas the Th2 subset functions more effectively as a helper for B-cell activation. The type of immune response to an antigen is generally influenced by the cytokines produced by the cells responding to the antigen. Differences in the cytokines secreted by Th1 and Th2 cells are believed to reflect different biological functions of these two subsets. See, for example, Romagnani (2000) Ann. Allergy Asthma Immunol., 85:9-18.
The Th1 subset may be particularly suited to respond to viral infections, intracellular pathogens, and tumor cells because it secretes IL-2 and IFN-γ, which activate CTLs. The Th2 subset may be more suited to respond to free-living bacteria and helminthic parasites and may mediate allergic reactions, since IL-4 and IL-5 are known to induce IgE production and eosinophil activation, respectively. In general, Th1 and Th2 cells secrete distinct patterns of cytokines and so one type of response can moderate the activity of the other type of response. A shift in the Th1/Th2 balance can result in an allergic response, for example, or, alternatively, in an increased CTL response.
It has been recognized for some time that a Th1-type immune response can be induced in mammals by administration of certain ISSs. The ISSs include sequences referred to as immunostimulatory sequences (“ISS”), often including a CG. See, e.g., PCT Publications WO 98/55495, WO 97/28259, U.S. Pat. Nos. 6,194,388; 6,207,646, and 6,498,148; and Krieg et al. (1995) Nature, 374:546-49. For many infectious diseases, such as tuberculosis and malaria, Th2-type responses are of little protective value against infection. Protein-based vaccines typically induce Th2-type immune responses, characterized by high titers of neutralizing antibodies but without significant cell-mediated immunity. Moreover, some types of antibody responses are inappropriate in certain indications, most notably in allergy where an IgE antibody response can result in anaphylactic shock.
In vertebrates, endothelial cell adhesion by granulocytes (eosinophils, basophils, neutrophils and mast cells) is followed by the release of inflammatory mediators, such as leukotrienes, major basic protein and histamine. In susceptible individuals, the resulting inflammation can damage affected individual tissues.
The most common pathologic inflammatory condition is asthma, which is characterized by marked eosinophil infiltration into respiratory airways, followed by inflammation-induced tissue damage. Routine treatment of such conditions is typically directed toward inhibiting the activity of inflammatory mediators released after granulocyte adhesion to endothelia (e.g., by delivering a corticoid composition to the affected tissues). Where the identity of an inflammation inducing antigen is known, some immune protection against further antigen challenge can be provided through immunization. However, although effective in stimulating production of neutralizing antibodies, canonical immunization does not effectively stimulate longer term cellular immunity. Moreover, antigen immunization stimulates individual production of IL-4 and IL-5. IL-5 encourages granulocyte adhesion to endothelia while IL-4 induces immunoglobulin switching to the IgE isotype at the risk of anaphylaxis.
With respect to allergic asthma, it has been shown that pretreatment with ISS inhibits allergen-induced airway eosinophilia and airway hyperresponsiveness in a mouse model for allergic asthma. Broide et al. (1998) J. Immunol. 161:7054. It also has been shown that this inhibition also correlates with ISS-induced down-regulation of Th2-type cytokine levels in the airways. Hessel et al., (2005) J. Exp. Med., 202(11):1563. These effects, however, focused on the direct effects of ISS treatment since the ISS treatment was given shortly before the allergen challenge. However, the effects of long-term treatment with ISS are remains largely unknown. In addition, a treatment for asthma that could confer long term benefits has not been well-characterized either. The invention disclosed herein provides teachings useful to address the foregoing.
All patents, patent applications, and publications cited herein are hereby incorporated by reference in their entirety.